| First Author | Banks GB | Year | 2020 |
| Journal | PLoS Genet | Volume | 16 |
| Issue | 11 | Pages | e1009179 |
| PubMed ID | 33175853 | Mgi Jnum | J:298623 |
| Mgi Id | MGI:6478107 | Doi | 10.1371/journal.pgen.1009179 |
| Citation | Banks GB, et al. (2020) Microutrophin expression in dystrophic mice displays myofiber type differences in therapeutic effects. PLoS Genet 16(11):e1009179 |
| abstractText | Gene therapy approaches for DMD using recombinant adeno-associated viral (rAAV) vectors to deliver miniaturized (or micro) dystrophin genes to striated muscles have shown significant progress. However, concerns remain about the potential for immune responses against dystrophin in some patients. Utrophin, a developmental paralogue of dystrophin, may provide a viable treatment option. Here we examine the functional capacity of an rAAV-mediated microutrophin (muUtrn) therapy in the mdx4cv mouse model of DMD. We found that rAAV-muUtrn led to improvement in dystrophic histopathology & mostly restored the architecture of the neuromuscular and myotendinous junctions. Physiological studies of tibialis anterior muscles indicated peak force maintenance, with partial improvement of specific force. A fundamental question for muUtrn therapeutics is not only can it replace critical functions of dystrophin, but whether full-length utrophin impacts the therapeutic efficacy of the smaller, highly expressed muUtrn. As such, we found that muUtrn significantly reduced the spacing of the costameric lattice relative to full-length utrophin. Further, immunostaining suggested the improvement in dystrophic pathophysiology was largely influenced by favored correction of fast 2b fibers. However, unlike muUtrn, mudystrophin (muDys) expression did not show this fiber type preference. Interestingly, muUtrn was better able to protect 2a and 2d fibers in mdx:utrn-/- mice than in mdx4cv mice where the endogenous full-length utrophin was most prevalent. Altogether, these data are consistent with the role of steric hindrance between full-length utrophin & muUtrn within the sarcolemma. Understanding the stoichiometry of this effect may be important for predicting clinical efficacy. |
